Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active. An example of such a pharmaceutical product is the non-steroidal anti-inflammatory drug Naproxen. The (S)-enantiomer is a potent anti-arthritic agent while the (R)-enantiomer is a liver toxin. It is therefore often desirable to selectively produce one particular enantiomer over its mirror image.
It is known that special precautions must be taken to ensure production of a desired enantiomer because of the tendency to produce optically inactive racemic mixtures; that is, equal amounts of each mirror image enantiomer whose opposite optical activities cancel out each other. In order to obtain the desired enantiomer or mirror image stereoisomer from such a racemic mixture, the racemic mixture must be separated into its optically active components. This separation, known as optical resolution, may be carried out by actual physical sorting, direct crystallization of the racemic mixture, or other methods known in the art. Such optical resolution procedures are often laborious and expensive and normally the yield of the desired enantiomer is less than 50% based on the racemic mixture feedstock. Due to these difficulties, increased attention has been placed upon asymmetric synthesis in which one of the enantiomers is obtained in significantly greater amounts. In particular, asymmetric synthesis processes facilitated by catalysis with transition metal complexes of single enantiomer chiral ligands (asymmetric catalysis) is finding ever increasing industrial applicability for pharmaceuticals and in other sectors.
Asymmetric hydroformylation of olefins is especially valuable for the synthesis of optically active products, since the reaction is a one-carbon homologation that also establishes a chiral center. Efficient asymmetric hydroformylation desirably affords the ability to control both regioselectivity (branched/linear ratio) and enantioselectivity. The optically active aldehyde that is produced in asymmetric hydroformylation can be further elaborated into other functional groups, either by subsequent reaction steps or via in situ reaction with other reagents.
Various asymmetric hydroformylation catalysts have been described in the art, see van Leeuwen, P. W. N. M. and Clayer, C., “Rhodium Catalyzed Hydroformylation”, Kluwer Academic Publishers, Dordrecht, 2000. For example, Stille, John K. et al., Organometallics 1991, 10, 1183–1189 relates to the synthesis of three complexes of platinum(II) containing the chiral ligands 1-(tert-butoxycarbonyl)-(2S,4S)-2-[(diphenylphosphino)methyl]-4-(dibenzophospholyl)pyrrolidine, 1-(tert-butoxycarbonyl)-(2S,4S)-2-[(dibenzophospholyl)methyl]-4-(diphenylphosphino)pyrrolidine and 1-(tert-butoxycarbonyl)-(2S,4S)-4-(dibenzophospholyl)-2-[(dibenzophospholyl)methyl]pyrrolidine. Asymmetric hydroformylation of styrene was examined with use of platinum complexes of these three ligands in the presence of stannous chloride as catalyst. Various branched/linear ratios (0.5–3.2) and enantiomeric excess values (12–77%) were obtained. When the reactions were carried out in the presence of triethyl orthoformate, all four catalysts gave virtually complete enantioselectivity (ee >96%) and similar branched/linear ratios. However, platinum hydroformylation catalysts are of limited utility due to their low catalytic activity and requirement for high CO/H2, i.e. syn gas, pressures.
Takaya, H., et al, J. Am. Chem. Soc. 1993, 115, 7033 reported the use of the mixed phosphine-phosphite ligand, BINAPHOS, for use in rhodium catalyzed hydroformylation. Enantioselectivities as high as 96% were observed for styrene hydroformylation, although the regioselectivity (branched/linear) was relatively low. Lambers-Verstappen, M. M. H. and de Vries. J. G, Adv. Synth. Catal., 2003, 345, 478–482 report application of BINAPHOS for the Rh-catalyzed hydroformylation of allyl cyanide; this process was only moderately selective, giving chiral aldehyde product of 66% ee and a branched/linear ratio of 72:28. Wills, M. and coworkers reported (Angew. Chem. Int. Ed., 2000, 39, 4106) the use of chiral diazaphospholidine ligand, ESPHOS, for Rh-catalyzed asymmetric hydroformylation of vinyl acetate. Enantioselectivities up to 92% ee were obtained for vinyl acetate. This ligand, however, was ineffective in the hydroformylation of styrene, giving a racemic mixture.
U.S. Pat. No. 5,491,266 to Union Carbide discloses highly effective chiral bisphosphite ligands for use in Rh-catalyzed asymmetric hydroformylation. Ligands prepared from optically active diols which bridge two phosphorus atoms were especially useful for a variety of olefin substrates. Preferred ligands, for example the prototype ligand known as Chiraphite, were prepared from optically active (2R,4R)-pentanediol and substituted biphenols. The highest regioselectivities and enantioselectivities (>85% ee) were observed with vinylarene substrates. Other substrates were hydroformylated with lesser selectivities.
Recently, a new type of ligand family was introduced where two optically active phosphite moieties are linked by achiral bridges (Cobley, C. J. et al., J. Org. Chem., 2004, 69, 4031 and Org. Lett., 2004, in press). The best ligand identified, Kelliphite, was shown to be enantio- and regioselective for the asymmetric hydroformylation of allyl cyanide (78% ee, b/l=18, at=35° C.) and vinyl acetate (88% ee, b/l=125, at=35° C.).
Despite the advances made in asymmetric hydroformylation technology as described above, existing ligands are limited in scope and predictability of performance. Accordingly, there is a need for wider range of chiral ligands for catalytic asymmetric hydroformylation, especially for multi-purpose ligands showing improved activity and selectivity profile, conferring favourable process economics across a range of substrates. Such substrates include, without limitation, styrene and other vinyl arenes, vinyl acetate and allyl cyanide. Another desired feature is that the ligand structure has modular design which can be systematically varied to obtain the best results for any given olefinic substrate. Lastly, for commercial applications, it is a requirement for favorable process economics that the chosen ligand for an asymmetric hydroformylation process can be synthesized efficiently from readily available raw materials. In seeking to design improved ligands, in general the known art teaches need for phosphite-containing or other hetero-phosphine ligands to achieve the level of activity required for rhodium-catalyzed hydroformylation, whereas diphosphine ligands (i.e. containing 2 phosphine group, in each of which the P atom bears three optionally substituted hydrocarbon substituents), often associated with asymmetric hydrogenation applications, are usually considered to less effective. Indeed, van Leeuwen and Clayer, idem, p. 131, have noted that “despite all the efforts made to apply diphosphines in asymmetric hydroformylation, the enantioselectivities of rhodium-diphosphine systems are not has high as those of rhodium-diphosphite or rhodium phosphine-phosphite systems.”
Landis, C. R. and coworkers have recently disclosed (PCT application 03/010174; Angew. Chem. Int. Ed. 2001, 40, 3432) the preparation of novel mono and diphosphines based on the 3,4-diazaphospholane ring structure as shown below. In specific examples of diphosphines reported to date, the substituent R2 is unsubstituted phenyl. In specific examples of monophosphines reported to date, the substituent R2 can be alkyl, unsubstituted aryl (e.g. phenyl, 2-naphthyl), unsubstituted heteroaryl (e.g. 2-furanyl), o-tolyl, or phenyl group substituted with OH, OAc, F, carboxyl or carboxamide groups.

These phosphines were shown to be easily synthesized from readily available materials and can be easily modified to alter their electronic and steric characteristics. Transition metal complexes of such phosphines have been shown to have utility as catalysts for asymmetric allylic alkylation (palladium complexes) and asymmetric hydrogenation (rhodium complexes). Monodentate phosphines were applied, for example, as ligands in allylic alkylation reactions (Clark, T. P.; Landis, C. R. J. Am. Chem. Soc. 2003, 125, 11792. Landis, C. R; Clark, T. C, Proceedings of the National Academy of Science 2004, 101, 5428–5432).